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Transcript
Methadone Maintenance A Practical Guide to Pharmacotherapy Ron Joe, M.D. VCH Medical Manager, Inner City Addiction (based on presentation by Dr. Jeffrey Dian) Objectives 1. Pharmacology of methadone 2. Practical application of pharmacology in methadone maintenance Part I Pharmacology of methadone Opioids • Natural derivatives of the poppy plant are opium, morphine, codeine • Heroin (diacetylmorphine) is a semi-synthetic derived from morphine • Synthetics are hydromorphone, oxycodone, meperidine, fentanyl, methadone Methadone Molecular Structure methadone codeine morphine Opioid Receptor Types • • • • Mu Kappa Delta ORL-1 G-Protein Coupled Receptor Opioid Receptor Effects • • • • Agonist Antagonist Agonist – Antagonist Partial Agonist Opioid Receptor Function • Mu1 (supraspinal analgesia, bradycardia, sedation) • Mu2 (respiratory depression, euphoria, physical dependence) • Delta (spinal analgesia, respiratory depression, dysphoria) • Kappa (sedation, spinal analgesia, respiratory depression) Antagonists • Naloxone • Naltrexone Blocks Mu, Kappa and Delta receptors Useful for methadone (or other opioid) overdoses. Beware of difference in half-life. Mu Agonists • • • • • • • • heroin (diacetylmorphine) morphine codeine hydromorphone oxycodone meperidine fentanyl methadone Partial Agonists • buprenorphine (partial Mu agonist, Kappa antagonist) • Suboxone (buprenorphine & naloxone 4:1) Suboxone has limited PharmaCare coverage for treatment of opioid dependence where methadone is contraindicated, e.g., for patients at high risk of, or QTc prolongation, or with a hypersensitivity to methadone, or where there has been inadequate response or intolerance to methadone. Methadone Basic Pharmacokinetics Excellent Oral Bioavailability (80-90%) Almost pure Mu Agonist Onset 30 mins Peak 2 – 4 hrs Very lipophilic 2 - 4 hrs Biphasic Elimination Effect on N-methyl d-aspartate (NMDA) Receptors • two isomeric forms “l” (levo) and “d” (dextro) • methadone in Canada contains a mix of the two isomeric forms • l-isomeric or (R)-methadone has an agonist effect on opioid receptors • d-isomeric (S)-methadone has an antagonist effect on NMDA receptors • meperidine, dextropropoxyphene, tramadol also have effect on NMDA receptors Methadone Biphasic Elimination analgesia (α elimination: 8–12 h) Plasma Level maintenance (β elimination: 30–60 h) Time Analgesic half-life is similar to short-acting opioids Maintenance half-life (withdrawal suppression) is prolonged Methadone Pharmacology • Potent Mu agonist (potential of single dose overdose) • N-Methyl-D-aspartic acid (NMDA) antagonist (blocks tolerance) • Delta agonist activity (blocks euphoria) • Analgesic half-life is similar to short-acting opioids • Blocks other opioids at higher doses • Analgesic properties of methadone differ significantly from maintenance properties • Maintenance half-life (withdrawal suppression) is prolonged (24 – 36 hours) • Accumulation with repeated use for pain can result in sedation and respiratory depression in the non-tolerant patient Steady State in Days 800 700 600 500 400 300 200 100 0 0 1 2 3 4 5 Time (multiples of elimination half-time) Dose Level Remains Constant Payte — Adapted from Goodman and Gilman 6 7 Methadone as an Analgesic • Short analgesic half-life (similar to morphine) • Usually prescribed q8h • Accumulated toxicity. Accumulation with repeated use for pain can result in sedation and respiratory depression in the non-tolerant patient • Potential for sedation and respiratory depression • When switching to methadone from another opioid agonist, there is a much more unpredictable degree of incomplete cross-tolerance than with other opioids • Standard analgesic equivalency tables cannot be used Methadone Side-Effects • • • • • • • • • • • • • Sedation Respiratory depression Hypotension Constipation / nausea or vomiting Stomach pain Gastroesophageal reflux syndrome Sleep disturbance Dysphoria Perspiration Pruritus Opioid-induced edema Endocrine effects Depressed libido Toxicity • • • • Concurrent use of sedative hypnotics Stimulants Alcohol Medications that interfere with methadone metabolism • Deteriorating liver function • QTc Prolongation (torsades de pointes) in high methadone doses (>150 mg) Methadone and QT Prolongation Factors which predispose to QTc prolongation and torsades de pointes •History of cardiac disease (arrhythmias, susceptible heart) •High methadone doses >150 mg daily •Endocrine or electrolyte disturbances •Co-administration of one or several QTc prolonging drugs* Recommend an ECG be recorded when one or more of the above factors are identified * Appendix T, Methadone Maintenance Handbook 2009 Methadone Metabolism • • • • Extensive bio-transformation in liver Metabolized by cytochrome P450-3A4 Some evidence of 2B6 and 2D6 metabolism Metabolites (mainly EDDP*) are essentially inactive • Metabolites and unchanged methadone are excreted in bile and urine • Metabolism does not rely on renal function *2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidine Drug Interactions Refer list of medications metabolized by cytochrome P450-3A4* • inhibitors • substrates • inducers Beware of cumulative effect of other central nervous system (CNS) depressants * Appendix S, Methadone Maintenance Handbook 2009 Inducer Examples Nevirapine efavirenz Protease Inhibitors Increased Clearance Tegretol Dilantin Anticonvulsants Poor Analgesia Withdrawal Smoking ETOH (Chronic) Other Inhibitor Examples erythromycin fluconazole ketoconazole Antibiotics Antifungal Agents Decreased Clearance Luvox Prozac Paxil amitryptylline SSRI’s /TCA’s Increased Serum Levels Toxicity ETOH (Acute) Other Part II Practical application of pharmacology in methadone maintenance Challenges • • • • high inter-individual variability high intra-individual variability (tolerance) interaction with other medications long elimination half-life Indications and Dose Forms Treatment of opioid dependence (maintenance) and treatment of pain (not first line) • 1 mg/ml most common, mixed with a drink made from flavoured crystals and ingested under supervision (“witnessed ingestion”) at the pharmacy • • • • • 10 mg/ml 1 mg tablets 5 mg tablets 10 mg tablets 25 mg tablets Is contraindicated in individuals with known hypersensitivity to the drug. It is also contraindicated in any situation where opioids are contraindicated such as patients with respiratory depression (in the absence of resuscitative equipment or in unmonitored settings), and in patients with acute bronchial asthma or hypercarbia. High risk for QTc prolongation. Initial Dose DEGREE OF TOLERANCE DOSE RANGE NON-TOLERANT 10 mg +/- 5 UNKNOWN TOLERANCE 20 mg +/- 5 KNOWN TOLERANCE 20 to 40 mg Methadone Initiation • There is no clear relationship between the amount of heroin used and the dose of methadone required to stabilize the patient • Doses are adjusted gradually until “tolerance threshold” is attained • Each dose will have a greater effect until steady-state is achieved (potential for accumulated toxicity) • Methadone induction is a dangerous period for risk of overdose Most programs recommend at least 5 days between dose adjustments in the range of 5–10 mg. More rapid dose escalations could be achieved by daily monitoring 3–4 hours post ingestion (peak methadone blood level) for the first 3–5 days after initiation or dose adjustment is required. This will reduce the risk of overdose. Prescribers should not allow weekends to interrupt this process and select a start date accordingly. Risk Factors for Methadone Toxicity • Use of other central nervous system (CNS) depressants • Lack of tolerance • Respiratory illness • Age • Liver disease • Use of medications which affect methadone metabolism Methadone Stabilization Doses It is important to stabilize a patient on an effective dose while avoiding the risk of overdose. An effective maintenance dose should have the following results: • Reduce or eliminate withdrawal symptoms • Reduction or eliminate drug craving • Will not induce sedation or drug craving • Block the euphoric effects of illicit opiods Most patients will receive stability on maintenance doses of 60– 120 mg daily. Methadone doses must always be individualized and based on clinical response. Heroin Use by Methadone Dose Payte — J.C. Ball, November 18, 1988 Retention in Treatment Payte — Adapted from Caplehorn and Bell: The Medical Journal of Australia Protocol for Missed Doses • • • • • • Utilize PharmaNet as a tool, communicate with pharmacist, hospital and other allied health care professionals Always review reasons for missed doses with patient (may need updated plan) There may be a rapid change in tolerance when methadone ingestion is interrupted or discontinued 1–2 days missed dose: Administer usual dose as long as no other contraindication 3–4 consecutive days missed: If dose is 30 mg or less, continue; if dose is greater than 30 mg, start at 50% of previous dose 5 or more consecutive days missed: Restart methadone and then titrate dose upwards as usual Tolerance • • • • • • Uncommon due to NMDA effect, but consider: Other drug withdrawal? Medication interactions? Environmental factors? Personal stressors? Alcohol? Rapid metabolizer (e.g., high dose, pregnancy)? Tolerance Strategies • • • • • • Cognitive behavioural interventions Increased contact, counselling, support Other drug withdrawal management Raise dose? Split dose (if stable)? Methadone blood levels? Split Doses Split doses are an alternative way of providing methadone to patients who have demonstrated rapid metabolism to methadone. These patients experience symptoms of opioid withdrawal from 4–6 hours before the next dose of methadone is administered in a 24-hour dosing schedule. A split-dose protocol involves administration of half the daily requirement of methadone every 12 hours. • Naturally high metabolizers • Pregnancy • Concurrent medication use (P450 3A4 enzyme inducers) Split doses should only be used in patients who have clinically demonstrated rapid metabolism. Because of the difficulty in ensuring witnessed ingestion twice daily, they should not be used simply when requested by a patient, particularly if stability has not been attained. Methadone Blood Levels • Peak/trough ratio is more important than individual serum methadone levels • Serum methadone pre-dose = Trough • Serum methadone 2–4 hours post-dose = Peak • Peak/trough ratio is usually 2.0 or less • Peak/trough ratio >2.0 suggests rapid metabolism Split Dose Simulation Single High Single Split Intoxication Normal Withdrawal Payte and Khun Split Dose Induction • DAY 1: – 100% of dose observed – 50% of dose to take in 12 hours • DAY 2: – 50% of dose every 12 hours Summary • Understanding pharmacology key • Many drug interactions are clinical relevant • Properly prescribed methadone is effective and safe • The correct methadone dose is highly variable • Frequent assessments are important